title: Chronic treatment with fluoxetine for more than 6 weeks decreases neurogenesis in the subventricular zone of adult mice.
abstract: BACKGROUND
  Recent studies indicate that chronic treatment with serotonergic antidepressants upregulates adult neurogenesis of the dentate gyrus (DG). In contrast, some studies claimed that there was very little alteration of neurogenesis in the subventricular zone (SVZ) by the antidepressants. Since almost all of those studies treated animals with drugs for 2 to 4 weeks as chronic treatment models of antidepressants, it is possible that antidepressant treatments for longer periods would affect adult neurogenesis in the SVZ.
  
  
  RESULTS
  In the present study, we examined the effects of long-term (up to 9 weeks) administration of fluoxetine (FLX), a selective serotonin reuptake inhibitor, on cell proliferation and survival in the DG and the SVZ of adult mice. As reported previously, in the DG of mice treated with FLX for 3, 6, or 9 weeks that were also injected with 5-bromodeoxyuridine (BrdU) in the last 3 days before perfusion, the numbers of Ki67- and BrdU-positive cells, which are cell proliferation markers, were significantly upregulated even at 3 weeks after the onset of the FLX treatments, and these increases were sustained in mice treated with FLX for 9 weeks. On the other hand, in the SVZ, we found a small, insignificant decrease in the numbers of Ki67- and BrdU-positive cells at 3 weeks, followed by highly significant decreases in the numbers of Ki67- and BrdU-positive cells at both 6 and 9 weeks. Furthermore, among olfactory newly generated cells that survived for 3 weeks after BrdU injection, the number of new cells was decreased at 9 weeks of FLX treatment.
  
  
  CONCLUSIONS
  These results demonstrate that long-term (more than 6 weeks) treatment with FLX has the opposite effect on neurogenesis in the SVZ than it does in the DG. The results also suggest that the decrease in neurogenesis in the SVZ might be involved in some aspects of the drugs' therapeutic effects on depression. In addition, our findings raise the possibility that some of the side effects of antidepressants might be mediated by decreased adult neurogenesis in the SVZ.
authors.affiliation: Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohira
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D064026:Calbindins; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002552:Cerebral Ventricles / Q000166:cytology* / Q000187:drug effects*; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000187:drug effects; D005473:Fluoxetine / Q000008:administration & dosage* / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013997:Time Factors
chemical_list: D064026:Calbindins; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D064030:S100 Calcium Binding Protein G; D005473:Fluoxetine; D001973:Bromodeoxyuridine